A Phase II, Multicentre, Multinational, Randomised, Assessor-Blind Trial to Investigate the Efficacy and Safety of Various Dosages of FSH-GEX™ in Comparison With 150 IU Gonal-f® in Women Undergoing ICSI Treatment
A Phase I, Mono-center, Placebo and Comparator Controlled, Single-blind, Randomized, Parallel Group, Clinical Study to Determine Multiple Dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of FSH-GEX(TM) Administered Subcutaneously in Healthy Pituitary-suppressed Female Volunteers
The aim of the current study is the pharmacokinetic and pharmacodynamic characterization of a multiple dose administration of FSH-GEX™ in healthy pituitary-suppressed female volunteers, in comparison with two marketed comparator products or placebo.
A Phase I, Monocenter, Randomized, Placebo and Comparator Controlled, Single Blind, Rising Dose, Clinical Study to Determine Single Dose Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Four Doses of FSH-GEX™ According to Adaptive Design (25, 75, 150 and 300 IU) Administered Subcutaneously in Healthy Pituitary-suppressed Female Volunteers
The aim of the current study was the pharmacokinetic and pharmacodynamic characterization of a single dose administration of four doses of FSH-GEX™ in healthy pituitary-suppressed female volunteers, in comparison with two marketed comparator products.
Effects of active immunization against a 13-amino acid receptor-binding epitope of FSHβ on fertility regulation in female mice.
作者: Fengyan Meng ; Huan Yao ; Jiaxin Li ; Yong Zhuo ; Guozhi Yu ; Guixian Bu ; Xiaohan Cao ; XiaoGang Du ; Qiuxia Liang ; Xianyin Zeng ; Xingfa Han
Follicle-stimulating hormone (FSH) is crucial for ovarian folliculogenesis and thus essential for female fertility. Here, we developed a novel FSH vaccine based on the tandem of a 13-amino acid receptor-binding epitope of FSHβ (FSHβ13AA-T) and used a mouse model to test its efficacy in female fertility regulation. Compared to placebo-immunized controls, FSHβ13AA-T vaccination: induced a marked (P < 0.05) antibody generation; reduced (P < 0.05) serum concentrations of FSH, inhibin B and 17β-estradiol; disrupted (P < 0.05) normal estrous cyclicity; delayed (P = 0.08) establishment of pregnancy; blocked (P < 0.05) folliculogenesis; and reduced (P < 0.05) litter size. Mechanistically, FSH vaccination reduced (P < 0.05) ovarian estrogen production by decreasing Lhcgr, Cyp19a1 and HSD3β1 expression, and suppressed ovarian follicular development by decreasing ovarian Fshr, Inhα, Foxo3a, Bmp15 and Cdh1 expression. Overall, vaccination of female mice with FSHβ13AA-T substantially disrupted FSH-dependent ovarian steroidogenesis and folliculogenesis, and caused subfertility. Therefore, vaccines based on FSHβ13AA-T have potential as anti-fertility/contraceptive agents in females.
2020-05-01·Theriogenology2区 · 农林科学
A novel follicle-stimulating hormone vaccine for controlling fat accumulation.
2区 · 农林科学
作者: Xingfa Han ; Zichao Guan ; Miaomiao Xu ; Ying Zhang ; Huan Yao ; Fengyan Meng ; Yong Zhuo ; Guozhi Yu ; Xiaohan Cao ; XiaoGang Du ; Guixian Bu ; Fanli Kong ; Anqi Huang ; Xianyin Zeng
Follicle-stimulating hormone (FSH) has been newly demonstrated to play a great role in promoting fat accumulation, providing a potential to target FSH for controlling fat accumulation and treating obesity. A short, 13-amino acid of FSHβ (FSHβ13AA) was indentified to be the FSH receptor-binding epitope in both humans and mice. By conservation analysis, we found such FSHβ13AA is highly conserved across species. Accordingly, we designed a new FSH antigen by synthesizing a tandem of FSHβ13AA (LVYKDPARPNIQK) and then conjugating it to ovalbumin (FSHβ13AA-T-OVA). Then, we tested its efficacy in suppressing fat accumulation in both ovariectomized and intact mouse models. Vaccination with this novel antigen emulsified in mild adjuvant, Specol, was highly effective in preventing ovariectomy-induced body weight gain and fat accumulation in mice (P < 0.01). Mechanistically, FSH vaccination treatment inhibited lipid biosynthesis by inactivating PPARγ adipogenic signaling pathway and simultaneously enhanced adipocyte themogenesis via upregulating UCP1 expression in both visceral and subcutaneous adipose tissues. Moreover, injection of this novel FSH vaccine also substantially reduced (P < 0.05) fat accumulation in both intact male and female mice. These actions result from the specific binding of the generated antibody to the β-subunit to block its action, rather than lowering the circulating levels of FSH, as evidenced by nearly no alterations in serum FSH levels in mice following FSH vaccination. Overall, we developed a novel FSH antigen and vaccine, and demonstrated it is highly efficacious in suppressing fat accumulation.
2019-01-16·The Cochrane database of systematic reviews2区 · 医学
Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.
2区 · 医学
作者: Nienke S Weiss ; Elena Kostova ; Marleen Nahuis ; Ben Willem J Mol ; Fulco van der Veen ; Madelon van Wely
Ovulation induction with follicle stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate.
To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS), and women who do not ovulate or conceive after clomiphene citrate.
In January 2018, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, the World Health Organisation clinical trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and Google Scholar. We checked references of in all obtained studies. We had no language restrictions.
All randomised controlled trials reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate, and undergoing ovulation induction with urinary-derived gonadotrophins, including urofollitropin (uFSH) in purified FSH (FSH-P) or highly purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotrophin (HP-HMG), or recombinant FSH (rFSH), or continuing clomiphene citrate. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinizing hormone, or letrozole.
DATA COLLECTION AND ANALYSIS:
Three review authors (NW, EK, and MvW) independently selected studies for inclusion, assessed risk of bias, and extracted study data. Primary outcomes were live birth rate per woman and multiple pregnancy per woman. Secondary outcomes were clinical pregnancy, miscarriage, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotrophin dose, and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the risk ratio (RR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria.
The review included 15 trials with 2387 women. Ten trials compared rFSH with urinary-derived gonadotrophins (three compared rFSH with human menopausal gonadotrophin, and seven compared rFSH with FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P. One trial compared FSH with continued clomiphene citrate.Recombinant FSH (rFSH) versus urinary-derived gonadotrophinsThere may be little or no difference in the birth rate between rFSH and urinary-derived gonadotrophins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; five trials, N = 505; I² = 9%; low-quality evidence). This suggests that for the observed average live birth per woman who used urinary-derived FSH of 16%, the chance of live birth with rFSH is between 13% and 28%. There may also be little or no difference between groups in incidence of multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; eight trials, N = 1368; I² = 0%; low-quality evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; eight trials, N = 1330; I² = 0; low-quality evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; seven trials, N = 970; I² = 0; low-quality evidence). We are uncertain whether rFSH reduces the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65, ten trials, n=1565, I² = 0%, very low-quality evidence).Human menopausal gonadotrophin (HMG) or HP-HMG versus uFSHWhen compared to uFSH, we are uncertain whether HMG or HP-HMG improves live birth rate (RR 1.28, 95% CI 0.65 to 2.52; three trials, N = 138; I² = 0%; very low quality evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51 to 8.91; four trials, N = 161; I² = 0%; very low quality evidence). We are also uncertain whether HMG or HP-HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; three trials, N = 102; I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; two trials, N = 98; I² = 0%; very low quality evidence), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; two trials, N = 53; very low quality evidence) when compared to uFSH.Gonadotrophins versus continued clomiphene citrateGonadotrophins resulted in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; one trial, N = 661; I² = 0%; moderate-quality evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with FSH was between 43% and 60%. There is probably little or no difference in the incidence of multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; one trial, N = 661; I² = 0%; moderate-quality evidence). Gonadotrophins resulted in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; one trial, N = 661; I² = 0%; moderate-quality evidence), and more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; one trial, N = 661; I² = 0%; moderate-quality evidence). None of the women developed OHSS.
There may be little or no difference in live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate between urinary-derived gonadotrophins and recombinant follicle stimulating hormone in women with polycystic ovary syndrome. For human menopausal gonadotropin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone we are uncertain whether one or the other improves or lowers live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate. We are uncertain whether any of the interventions reduce the incidence of ovarian hyperstimulation syndrome. We suggest weighing costs and convenience in the decision to use one or the other gonadotrophin. In women with clomiphene citrate failure, gonadotrophins resulted in more live births than continued clomiphene citrate without increasing multiple pregnancies.
SAN JOSE, Calif. – Although CAR-T therapies have only been approved for the treatment of B-cell blood cancers, tiny ITUS believes it is on track to develop a CAR-T treatment for solid tumors.
On Nov. 14, the California company struck a deal with Pennsylvania-based The Wistar Institute for a Chimeric Antigen Receptor T-Cell (CAR-T) technology aimed initially at treating ovarian cancer and eventually additional solid tumors.
Amit Kumar, chief executive officer of ITUS, told BioSpace in an exclusive interview that he believes the licensed technology has a “unique approach” to targeting ovarian cancer. Instead of using an antibody fragment, like the B-cell targeting CAR-Ts, the engineered T-cells being developed by ITUS will use the Follicle Stimulating Hormone (FSH) to target ovarian cells that express the FSH-Receptor.
Kumar said the CAR-T treatment will most likely will used to treat refractory ovarian cancer patients for which there are few options.
“This approach is different from what others are trying,” Kumar said. “The Follicle Stimulating Hormone is exclusive to the ovaries. It’s not found on the other cells in the body. Attacking this unique receptor on the ovarian cancer cell will be a powerful approach.”
So far the animal studies performed by ITUS are showing promise, Kumar said. Next year the company intends to complete data studies and Investigative New Drug Application so they can take the program into the clinic and begin work on humans. That will hopefully lead to confirmation of ITUS’s theories about FSH, Kumar said. It will also likely lead to other solid tumor targets, particularly in prostate and pancreatic cancers.
The expectation is if the ITUS approach works on solid tumors the value to cancer patients will be immense because there are more solid tumors than blood cancers. Case in point, Kumar said, the ovarian cancer market dwarfs the B-cell cancer market.
The American Cancer Society estimates for 2017 that about 22,440 women will receive a new diagnosis of ovarian cancer and about 14,080 women will die from ovarian cancer. On average, the five-year relative survival for all types of ovarian cancer is about 45 percent. If it’s found early and treated, relative survival rates increase to about 92 percent.
ITUS formed a subsidiary, Certainty Therapeutics, to develop and commercialize the CAR-T technology. Days after ITUS licensed the CAR-T technology, the company and its new subsidiary entered into a research and development agreement with Moffitt Cancer Center to advance the program and help drive it into the clinic. Kumar said the agreement is in line with ITUS’s goal of remaining a lean company.
He said the company’s plan is to work with partners at every level. The deal with Moffitt gives ITUS access to Moffitt’s laboratories and a “group of stellar world-class physicians and researchers who can do the work,” Kumar said.
This strategy will allow the company to work with multiple research institutes and advance the ITUS technologies to a stage where they can be partnered with corporate allies.
In addition to the CAR-T program, ITUS is also moving forward with its Cchek cancer detection platform, a program invented by Kumar. The program is a liquid biopsy that will measure immune cells that indicate cancer development. Kumar said they believe this technology will work on every type of tumor. Instead of measuring cancer, the Cchek platform will measure the body’s immune response to cancer.
The Cchek platform should be able to determine if a traditional biopsy is required. Kumar said 95 percent of biopsies are negative, which means that many patients have gone through minor traumas from some of the tests for a negative result.
“There’s all sorts of issues with a biopsy. Our goal is to develop a test that’s confirmatory. Before that needle gets stuck in your lung (for a lung cancer biopsy), we want a simple blood-based test. From that test they can tell if a biopsy is necessary,” Kumar said. “If we can eliminate 25 to 50 percent of biopsies, it’s a home run.”
ITUS is initially developing its Cchek technology with a focus on prostate and breast cancers. Kumar estimated that the company is about 18 to 24 months away from taking it to the U.S. Food and Drug Administration for approval and possible commercialization. During this time period, Kumar hopes ITUS can find corporate partners to help commercialize the test.
Kumar, the former head of CombiMatrix Corporation, became CEO of ITUS in July. He took over after it had shifted its focus to almost exclusively developing cancer therapies. Over the next few months, the company will primarily focus on its two programs while Kumar begins to meet with investors and media to talk about the company.
“We’re still under the radar right now, and we feel that we’ll be coming out pretty soon,” Kumar said.